Methods for producing alkoxynaphthoylalkanoic acids



Patented Dec. 23, 1952 UNITED STATES PATENT OFFICE METHODS FOR PRODUCINGALKOXYNAPIL THOYLALKANOIC ACIDS Robert R. Burtner, Skokie,.lll.,assignorto: G. D. Searle & 00., Chicago, 111., a corporation ofIllinois- Noxnrawing: Application-October 12; 1950, SerialNo; 189,891

stclaimsr (01. 260 -520) at: low temperatures, that is, at ''to' C. in

tetrachloroethaneand related halogenated aliphatic hydrocarbons, 0rincarbon disulfide. Unless highly purified halogenat d solvents, whichare-not commercially available, are used these procedures give low:yields of acids which are contaminatedwith undesirable'sideproducts,resulting from interaction of the alkoxynapthalenes and active halogencompounds found in the commercial tetrachloroethane. With-carbon di-'sulfide. the acids contain sulfur-containing impurities;Consequentlythe-methods of the prior art, commercial practice, requirecomplicated purification procedures and hence give'low yieldsofmaterials of sufficient purity for medicinal purposes.

I? have discovered. that the use: of benzene as the solvent. andconductionof the reaction" at elevated temperatures: results ingreatlyincreased yields of purer products. This result is-qu-ite unexpectedbecause, as is wellknown, benzeneitself undergoes Friedel-Crafts typereactions. Furthermore it has'been reported that such reactions arepreferably carried out at low temperatures, particularly since elevatedtemperatures induce dealkylation of the product.

My discovery has resulted in feasible methods for synthesizing in highpurity compounds of the general type for use in the medical'arts,wherein R represents a lower alkyl radical and Alk represents aloweralkylene radical.

The substances produced by my methods are useful as medicinal agents,particularly as choto prepare such acids without the use of halogenatedaliphatic hydrocarbons and by avoiding the undesirable. side reactionswhich result from such materials. Other objects will be apparent tothose skilled in the art.

According to my discovery, anhydrides of dibasic aliphatic acids ofstructural formula where Alk represents an alkylene radical containingfrom two to five carbon atoms, are condensed'with an e-alkoxynaphthaleneof the formula where R represents a lower alkyl radical, in the presenceof a Friedel-Crafts type catalyst in anhydrous benzene. Similarlythehemi-acid halidehemi-lower alkyl ester of the formula maybe used,wherein X is halogen and Z is lower alkyl. In such cases the resultingester is saponilied to produce the desired acid. The preferredFriedel-Crafts type catalyst for this reaction is anhydrous aluminumchloride. Other related catalysts are those including anhydrous aluminumbromide, anhydrous sodium-aluminum chloride; boron'trifluoride,anhydrous ferric chloride, anhydrous stannic' chloride, hydrogenfluoride, sulfuric acid, and the like.

In practice I have found that equivalent amounts ofrthe.dibasic'acid'anhydrides and of the alkox-ynaphthalenes may be used withtwo or slightly more thantwo equivalents of the Friedel- Crafts typecatalyst. Excesses of the alkoxynaphthalenes are acceptable althoughundesirable from the cost viewpoint. Likewise, considerably more thantwo moles of the Friedel-Crafts type catalyst may be. used although thisis generally economically undesirable. When the hemi-acid halidehemi-alkyl. ester of the dibasic acid is used, only one or slightly morethan one equivalent of catalyst is required.

The reactions are conducted at elevated temperatures at the range of.60-C. for a brief period of time, that is, from one-half to three hours.After the reaction has been completed at elevated temperatures, theproducts are isolated-by decomposing the reaction mixture withdilute-acid-or preferably with ice and acid. The solvent is thenremoved, preferably by steam distillation, and the desired products areinsoluble the organic acid that results can then "be separated byfiltration and drying.

My invention is disclosed in further detail by the following examplesbut is not to be construed as limited thereto in spirit and in scope.Relative quantities of materials are given in parts by weight, andtemperatures are recorded in degrees oentigrade.

- "Example! 395 parts of a-methoxynaphthalene and 265 parts of succinicanhydride are dissolved in 8,000 parts of dry benzene at roomtemperature. The resulting solution is stirred and 710 parts ofanhydrous aluminum chloride are added over a period of twenty minutes.During the addition the temperature of the reaction mixture rises toabout 60-70 C. After the addition the reaction mixture is stirred forfifteen or twenty minutes at 60-70 C. and then refluxed for one hour.The hot reaction mixture is then poured onto a mixture of 5,000 parts ofice and 900 parts of concentrated hydrochloric acid. The benzene isremoved by steam distillation and the hot aqueous residue is filtered toremove the insoluble /3( 1- methoxyi-naphthoyl) propionic acid. Theresidue of the latter is dried and then dissolved in 16,000 parts of hotwater containing 300 parts of sodium carbonate. The hot solution istreated with activated charcoal, filtered while hot, chilled andacidified. The residue of purified acid is collected on a filter, washedwith water, and dried at 65 C. A yield of 552 parts of purified ,8-(1-methoxy-i-naphthoyl)propionic acid, melting at 172-173 C. is obtained.

Example 2 An experiment, conducted as in Example 1, but using eighttimes the amounts of reagents and solvents gave a yield of 4.470 partsof fi-(l-methoxy 4 naphthoyDpropionic acid, melting at 172 C.

Example 4 To a solution of 648 parts of a-methoxynaphthalene and 470parts of glutarie anhydride in 5,000 parts of benzene at roomtemperature are added 1,090 parts of anhydrous aluminum chloride withgood agitation over a period of about forty minutes. The temperature ofthe mixture rises to about 70 C. during the addition. The mixture isrefluxed for one hour after the addition and then poured onto an excessof ice and hydrochloric acid. The solvent is removed by steamdistillation and the residue is chilled and filtered to remove.theprecipitate of v-(l-methoxy-l-naphthoyl) butyric acid. The latter istaken up in 10,000 parts of water at 85 C. con- '4 taining 500 parts ofsodium carbonate. The solution is cooled to room temperature, extractedwith ether to remove any unreacted a-methoxynaphthalene, warmed to' 855C., treated with decolorizing charcoal, chilled, and acidified. Aprecipitate of 438 parts of purified 'y-(l-methoxy- 4-'naphthoyl)butyricacid is obtained, which melts at 164-166 C. Recrystallization frommethanol with the aid of activated charcoal gives material melting at167 C.

Eztample 5 Example 6 To an agitated suspension of 71 parts of anhydrousvaluminum chloride in 400 parts ;of dry benzene at room temperatureisadded in 45 minutes a solution of 79 parts of a-methoxynaphthalene and75 parts of B-carbomethoxypropionyl chloride in 100 parts of drybenzene. The temperature rises to about -70 C. The mixture is thenstirred for about 6 hours without additional heat. It is decomposed byaddition to 1000 parts of ice and- 90 parts of concentrated hydrochloricacid.- The benzene layer is separated, washed with water, dried andevaporated; The residue is saponified by treatment with a boilingsolution of 4.0 parts of sodium hydroxide in 330 parts of methanol for30 minutes. The methanol is stripped oil under vacuum and the residue istaken up in 2000 parts of water. The resulting solution is made acidwith concentrated hydrochloric acid,warmed to about 90 C. and filteredwhile hot. The precipitate of p-(l-methoxy-inaphthoyDpropionic acid isWashed with hot water and dried; There is thus obtained a yield of 110parts of'product melting at 171-173 C.

I claim:

1. The method of producing an alkoxynaphthoylalkanoic acid of theformula lyst in benzene at elevated temperature in the range of 603-100?C. and separating the. alkoxynaphthoylallranoic acid.

2. The method of thoylalkanoic acid of the formula producing analkoxynaphwherein All: is an alkylene radical of two to five carbonatoms which comprises reacting an amethoxynaphthalene with an anhydrideof a dibasic saturated aliphatic acid of four to seven carbon atoms inthe presence of anhydrous aluminum chloride in benzene at elevatedtemperature in the range of 60-100 C. and separating themethoxynaphthoylalkanoic acid.

4. The method of producing e-(l-methoxyinaphthoyDpropionic acid whichcomprises reacting a-methoxynaphthalene with succinic anhydride in thepresence of anhydrous aluminum chloride in benzene at elevatedtemperature in the range of 60-100 C. and separating thep-(lmethoXy-4-naphthoyl)propionic acid.

5. The method of producing -(1-methoxy-4- naphthaoybbutyric acid whichcomprises reacting a-methoxynaphthalene with glutaric anhydride in thepresence of anhydrous aluminum chloride in benzene at elevatedtemperature in the range of 60-l00 C. and separating the -(1-methoXy-4-naphthoyl) butyric acid.

6. The method of producing 6-(1-methoxy-4- 6 naphthoyDvaleric acid whichcomprises reacting a-methoxynaphthalene with adipic anhydride in thepresence of anhydrous aluminum chloride in benzene at elevatedtemperature in the range of -100 C. and separating the 5-(1-methoxyi-naphthcyl) valeric acid.

7. The method of producing an alkoxynaphthoylalkonic acid whichcomprises reacting an a-(lower alkoXy)-naphthalene with a member of thegroup consisting of an acid anhydride of an acid of the formula whereinAlk is an alkylene radical of two to five carbon atoms, and an acidhaline oi the formula wherein X is halogen and Z is lower alkyl, in thepresence of a Friedel-Crafts catalyst in benzene at elevated temperaturein the range of Gil- C. and separating the alkoxynaphthoylalkanoic acid.

8. The method of producing p-(l-methoxy- 4-naphthoy1)propionic acidwhich comprises reacting a-methoxynaphthalene withfl-carbomethoxypropionyl chloride in the presence of anhydrous aluminumchloride in benzene at elevated temperature in the range of 60-100 C.,saponifying the resulting ester and separating the [i-(1-methoxy-4-naphthoy1) propionic acid.

ROBERT R. BURTNER.

REFERENCES CITED The following references are of record in the file ofthis patent:

Desai et al., Chem. Abstracts, vol. 31, col. 3038 (1937) Beyer, Chem.Abstracts, vol. 32, col. 4556-4557 (1938).

Burtner et al., abstract of S. N. 780, 572, Official Gazette, vol. 634,p. 312 (1950).

1. THE METHOD OF PRODUCING AN ALKOXYNAPHTHOYLALKANOIC ACID OF THEFORMULA